Anti-depressant compositions and methods



United States Patent 3,223,586 ANTI-DEPRESSANT COMPOSITIONS AND METHODSFrank J. Villani, West Caldwell, NJ., assignor to Schering Corporation,Bloomfield, N.J., a corporation of New Jersey No Drawing. Filed June 28,1963, Ser. No. 291,295 7 Claims. (Cl. 167-65) This application is acontinuation-in-part of my copending application Serial No. 161,766,filed December 18, 19611, now US. Patent 3,188,347.

This invention relates to-(4-dimethylaminocyclohexyl)-dibenzo-[a,d]-cyclohepta-[1,4J-diene, thenontoxic acid addition salts thereof, and to the processes for makingand using such compositions.

In its composition of matter aspect, the invention resides in theconcept of the chemical compound 5-(4-dimethylaminocyclohexyl) dibenzo[a,d] cyclohepta- 1,'4]-diene having the structural formula:

which concept includes the cis and/ or trans isomers thereof, as well asthe non-toxic acid addition salts thereof. The nomenclature assigned isin accordance with the subject index of Chemical Abstracts (ll956)wherein such compounds are named as derivatives of dibenzo-[a,d]-cyclohepta-[:1,4]-dienes.

The tangible embodiments of the compositions of matter of this inventionpossess the inherent applied use characteristic of exerting ananti-depressant effect in mammals. Therefore, in its process-of-useaspect, this invention embraces the concept of administering atherapeutically effective quantity of a5-(4-dimethylaminocyclohexyl)-dibenzo-[a,d]-cyclohepta-[l,4]-diene toachieve an anti-depressant effect in depressed-state mammals.

The manner and process of making and using the invention will now bedescribed so as to enable one skilled in the art to make and use thesame.

Preferably, 5 (4 dimethylaminocyclohexyl)dibenz-o-[a,d]-cyclohepta-[-1,4]-diene is prepared by a condensationreaction between a dibenzo-[a,d]-cyclohepta [l,-4]-diene-5-one (or adibenzo-[a,d]-cyclohepta-[1, 4]- triene-S-one) and an organometallicderivative of p-halodimethylaniline to formS-hydroxy-S-(p-dimethylaminophenyl) dibenzo [a,d]-cyclohepta [1, 4]diene (or t-riene) which is catalytically reduced to the desiredcompound. Optionally, the desired compound may also be prepared bycondensing a magnesium, lithium, or zinc derivative ofd-ibenzo-[a,d]-cyclohepta-[l,4]-diene with a4d.imethylaminocyclohexanone to produce 5-(4-dime-thylamino 1 hydroxycyclohexyl) dibenzo [a,d] cyclohepta-[1,41-diene which is dehydrated andreduced to the desired compound.

The initial condensation reaction can readily be effected by contactingthe reactants together at either room temperature or preferably atelevated temperatures in an inert anhydrous medium using such inertorganic solvents as tetrahydrofuran, dioxane, ether, toluene, xylene,cnmene, tetralin, and the like. Preferably, the reaction is eifected atabout the reflux temperature of the reaction mixture.

The dehydration of the carbinol obtained by the condensation of the5-organometallic compound with the dimethylaminocyclohexanone can beeffected by conventional technique, such as by heating the substance inthe presence of alcoholic hydrochloric acid, sulfuric acid, Zincchloride, phosphorous oxychloride, and the like. Conventional techniquesmay also be used for the hydrogenation of the dehydrated product.Preferably, the substance is hydrogenated under pressure in the presenceof a catalyst such as platinum oxide or Raney nickel.

Although it is more convenient to produce the desired compound by theforegoing methods, it should also be realized that, depending on thestarting materials available, various modifications may be called for.The following reactions may serve to illustrate the various approachesone skilled in the art might take to form the compound of thisinvention: (11) condensation of S-lithiodibenzo [a,d] cyclohepta [1,4]diene with 4-methoxycyclohexanone to form 5-(4'-methoxycyclohexanol)-dibenzo-[a,d]-cyclohepta-[1,4]-diene which is dehydrated to form 5 (4methoxycyclohexenyl) dibenzo [a,d]- cyclohepta-[IA]-diene. This product,in turn, is hydrogenated and reacted with hydrobromic acid to form 5-(4' hydroxycyclohexyl) dibenzo [a,d] cyclohepta- [1,4]-diene which isoxidized and the resulting oxidation product reacted with dimethylamineto form the desired compound; 2) catalytic reduction of5(p-dimethylamino phenyl)-dibenzoa,d] -cyclohepta- 1 ,4] -diene withplatinum oxide in the presence of ethanolic hydrochloric acid; (3)reduction of5-(p-dimethylaminophenyl)-dibenzo-[a,d]-cyclohepta-[1,4]-diene withlithium metal in ethylamine to the tetrahydro derivative followed by thecatalytic hydrogenation of the p-dimethylaminocyclohexenyl moiety to thedesired compound; (4) addition reaction of p-anisylmagnesium bromidewith dibenzo- [a,d]-cy-clohepta-[ IAJ-diene-S-One followed byhydrogenation in the presence of platinum oxide and ethanol (effectinghydrogenolysis and simultaneous hydrogenation), demethylation of theresulting ether to the hydroxy compound, oxidation to the ketone, andreductive alkylation of the ketone in the presence of Raney nickel anddimethylamine to the desired compound.

While the foregoing methods are suitable for the preparation of thecompound of this invention, the following specific exemplificationillustrates the best mode contemplated by the inventor for thepreparation of the compound of this invention.

EXAMPLE 1 5 4 -dimethylam inocyclohexyl -dib enzo- [a,d] cyclohepta-[1,4] -dz'ene Step A.-A solution of 40 g. of p-bromcdimethylaniline in400 ml. of anhydrous ether is added portionwise to a suspension of 2.75g. lithium shot in 50 ml. of ether. The mixture is refluxed on a steambath with stirring for 4 hours, after which time a solution of 20.8 g.of dibenzo- [a,d]-cyclohepta-[1,4J-diene-5-one in ml. of ether is addedand the reaction mixture is stirred and heated on the steam bath for anadditional 4 hours, and is then allowed to stand overnight. The darkpurple reaction mixture is decomposed with ice water and the organicmaterial is extracted with ether. The ether extracts are combined andextracted thoroughly with 10% aqueous hydrochloric acid and the acidextracts are combined and made basic with ammonium hydroxide solution.The precipitated product is extracted with chloroform and the chloroformis removed by concentration on the steam bath. The crudeS-hydroxy-S-(p-dimethylaminophenyl)-dibenzo-[a,d]-cyclohepta-[l,4]-diene residue is triturated withpetroleum ether and the product is recrystallized from a large volume ofhexane after Darco clarification.

Step B.Ten grams ofS-hydroxy-S-(p-dimethylaminophenyI)-dibenzo-[a,d]-cyclohepta-[1,4]-dienedissolved in 250 ml. of ethanol containing 2.4 ml. of concentratedhydrochloric acid is reduced in a Parr hydrogenator at room temperatureand 60 p.s.i. initial hydrogen pressure in the presence of 0.5 g. ofplatinum oxide catalyst. After filtering ofi the catalyst, the filtrateis concentrated to dryness and the residue is dissolved in water andmade basic with ammonium hydroxide. The product is extracted withchloroform andafter removal of the chloroform, the product is distilledas a viscous yellow oil.

Step C.--The product of Part B of this example is adsorbed on alumina ina chromatographic column. The column is eluted first with apentane-benzene (95-5%) solvent system. After the first elution iscomplete the column. is eluted with a pentane-ether (50-60%) solventsystem. The pentane-ether eluate is evaporated to dryness and theresidue recrystallized from hexane to yield white crystalline5-(4-dimethylaminocyclohexyl)-dibenzo- [a,d]-cyclohepta-[l,4]-diene,M.P. 97-100 C.

The pentane-benzene eluate is evaporated to dryness and the residuerecrystallized from hexane to yield 5-(4- dimethylaminocyclohexyl)dibenzo [a,d] cyclohepta [1,4]-diene, M.P. 90-91 C., the stereochemicalisomer of the pentane-ether eluate product.

EXAMPLE 2 5 -(4-dimethylaminocyclohexyl -dibenz- [a,d cyclohepta- [1,4]-diene hydrochloride A saturated solution of hydrogen chloride inethanol is added to a solution containing 7.5 g. of5-(4-dimethylaminocyclohexyl) dibenzo [a,d] cyclohepta- [1,4] diene,M.P. 97-100 C. until precipitation is complete. The precipitated productis filtered, washed with ether, and recrystallized from a 5 05 0%mixture of absolute ethanol and absolute ether to yield the whitecrystalline 5-(4- dimethylaminocyclohexyl)-dibenzo [a,d] cyclophepta-[2,4]-diene hydrochloride, M.P. 272274 C.

Other acid addition salts of 5-(4-dimethylaminocyclohexyl)-dibenzo[a,d]cyclohepta [1,4]diene, such as those formed from hydrobromic acid,phosphorous acid, sulfuric acid, acetic acid, tartaric acid, maleicacid, citric acid, succinic acid, and the like, may be prepared byanalogous procedures well-known to those skilled in the art.

Having set forth the details as to how the compounds of this inventionare to be made, the inventor will now set forth the manner and method ofusing such compounds.

While moderate success has been achieved in the treatment ofpsychopharmacological depression in mammals with some of the presentlyused anti-depressant compounds, the success has been limited to arelatively small percentage of the depression-states. As a consequence,there exists a need for agents which are more generally applicable, aswell as for agents which produce fewer undesirable autonomic andneurologic side-effects. therefore an object of this invention toprovide .a novel composition of matter that will satisfy such needs.Such an object is accomplished by the composition of this inventi-on.

Using standard techniques and standard procedures, the toxicity of thecompound of this invention was first evaluated in mice, and'then indogs, with favorable results. Effective antidepressant activity inmammals may be evidenced by laboratory and clinical techniques wherein adepressed subjects reaction to the compositions of this invention iscompared to the subjects reactions to chemical compounds known to havean anti-depressant effect. From these tests (tests, for example, such asthose found described or referred-to in such articles as by D. R.Maxwell, H. T. Palmer, Nature 191, 84 (-1961) and by L. Stein, 1.Seifter, Science 134, 286 (1961)), it has been concluded that thecompositions of this invention, in their effect upon the central nervoussystem, cause stimulated effects and altered performance of depressedsubjects with Z few side-effects, and therefore, are useful in thetreatment of psychopharmacological depression in mammals caused by bothlaboratory-induced conditions and by multifarious modern-day stimuli.

The effective dosage of the active ingredient of the composition of thisinvention depends upon the severity, the stage, and the individualcharacteristic of each case and will be determined by the attendingdiagnostician. Generally, a dosage range of from about 0.1 mg. to about15 mg. per kg. of body weight per day constitutes the overall range,with a range of from about 0.1 mg. to 5 mg. per kg. per day for thepreferred form of active ingredient.

The compounds of my invention may be used in the form of pharmaceuticalpreparations which contain the new compound in admixture with apharmaceutical carrier suitable for enteral or parenteraladministration. In their preferred dosage unit forms the activeingredient is 7 present in amounts of about 5 to 150 mg. Suchpreparations may be in solid forms, as for example tablets and capsules,or in liquid forms, as for example syrups, elixirs, emulsions andinjectables.

In the formulation of pharmaceutical preparations there can be employedsuch substances which do not react with the compounds, as for example,Water, gelatin, lactose, starches, magnesium stearate, talc, vegetableoils, benzyl alcohols, gums, polyalkylene glycols, and petroleum jelly.

The following examples will serve to further exemplify the nature ofthese various formulations. These examples, however, are not intendedand should not be construed in any way so as to limit the scope of theproduct formulation.

Purified water, q.s. to make 1.0 liter.

Dissolve successively the 5-(4-dirnethylaminocyclohexyl)dibenzo-[a,d]-cyclohepta-[1,4]-diene hydrochloride, citric acid, sodiumcitrate, sodium benzoate and sucrose in suflicient water to makeapproximately 900' ml. Add the sweet orange peel tincture and sufficientwater to make the product measure one liter. Agitate until uniform.Filter, using an appropriate filter aid if necessary, until the productis clear.

EXAMPLE 4 [Injectable, 10 mg./ml.]

Ingredient: Quantity, gm. 5 (4 dimethylaminocyclohexyl)-dibenzo-[a,

d]-cyclohepta-[1,4]-diene hydrochloride 10.0

Sodium chloride, U.S.P 9.0 Methylparaben 1.8 Propylparaben 0.2 Benzylalcohol, R.G. 9.0

Water for injection q.s. to make 1.0 liter.

Dissolved methyl and propylparabens in the benzyl alcohol with the aidof heat and agitation. Add this solution to a volume of Water forinjection equal to of the desired final volume and dissolved withagitation. Add and dissolve the sodium chloride. Add and dissolve the5-(4-dimethylaminocyclohexyl)-dibenzo-[a,d]- cyclohepta-[1,4]-dienehydrochloride. Add water for injection q.s. to final volume. Filterasceptically through appropriate sterile filter. Fill asceptically into10 ml. rubber stopperedvials. I

,5. EXAMPLE [Tablets, 25 mg] Ingredient: Quantity, gm.

5 (4 dimethylaminocyclohexyl) dibenzo- [a,d] cyclohepta-[1,41-dienehydrochloride 250.0

Lactose 1000.0 Corn starch 600.0 Corn starch as paste 50.0

Mix the 5- (4-dimethylaminocyclohexyl)-dibenzo-[a,d]-cyclohepta-[1,4]-diene hydrochloride, lactose and corn starch, and passthrough a pulverizing mill if necessary. Granulate the mix with thestarch paste and add additional water if necessary to make a dampgranulation. Pass the granulation through an impact mill to produce 8-12mesh granules. Spread the granulation on trays and dry in a draft-ovenat 35-40 C. Reduce the dried granulation to 16-24 mesh. Blend theforegoing 1900 grams of wet granulation with 80.0 gm. of cornstarch and20.0 g. of magnesium stearate until a uniform mixture is obtained.Compress to 200 mg. tablets on inch round punches.

Also, by certain modifications in the 5-position substituents of thedibenzocycloheptene nucleus it is determined by pharmacologicalevaluation that the toxicity of and the anti-depressant activity of theso-modified composition is not materially affected. For example, 5 (4dimethylaminocyclohexylidene) dibenzo [a,d]- cyclohepta [1,4] diene,5-(4-dirnethylaminophenyl)- dibenzo [a,d] cyclohepta [1,4] diene,S-hydroxy-S- (4-dimethylaminophenyl) dibenzo [a,e] cyclohepta-[1,4]-triene, 5 hydroxy 5 (4-dimethylaminophenyl)-dibenzo-[a,d]-cyclohepta-[l,4]-diene exhibit the herein disclosedanti-depressant activity. Such modifications to the molecular structureof the inventive concept herein described are, therefore, equivalents ofthe subject matter sought to be patented, and as such are fully embracedby the inventive concept herein described and claimed.

The following examples illustrate the methods employed for thepreparation of the modified compositions of matter of the invention.

EXAMPLE 6 5-(4'-dimethylaminocyclohexylidene)dibe zo-[a,d]-

cyclohepta- [J ,4] -diene To a solution of 2.5 g. sodium metal in 200ml. of ethanol add a solution of 33.5 g. ofS-hydroxy-S-(p-dimcthylaminophenyl) dibenzo [a,d] cyclohepta-[1,4]-dienein 200 ml. of absolute ethanol, and stir the resulting mixture for twohours at room temperature. Dropwise, add 14.2 g. of methyl iodide to thestirred mixture and reflux the resulting mixture for 8 hours. Evaporateoff the alcohol, in vacuo, suspend the residue in water, and extractwith ether. Dry and evaporate off the ether solvent, and recrystallizethe resulting residue from dilute methanol.

Dissolve the so-obtained S-methoxy 5 (p-dimethylaminophenyl) dibenzo[a,d] cyclohepta-[1,41-diene in 150 ml. of glacial acetic acid andhydrogenate at 50 60 C. in the presence of rhodium (5%) on alumina, at ahydrogen pressure of about 4.3 atmospheres, until the theoreticalquantity of hydrogen is absorbed. Filter 01f the solids, and evaporatethe solution to dryness.

Add 150 ml. of 48% hydrobromic acid to the residue and reflux theresulting mixture for 24 hours, and remove the solvent by concentrationin vacuo.

Dissolve the resulting residue in water, make basic with sodiumhydroxide and extract the product with chlorofor-m. From the chloroformextract, the solvent is stripped off and the residue distilled to yieldthe desired 5 (4' dimethylaminocyclohexylidene) dibenzo [a,d]-cyclohepta-[1,4]-diene, B.P. 203207/ 1.5 mm.

6 EXAMPLE 7 5- (4-dimethylaminocyclohexylidene)-dibenz0-[a,d]-

cyclohepta-[1,41-diene Add a solution composed of 12.7 g. of n-butyllithium, 100 ml. of ether and 100 ml. of tetrahydrofuran to a solutioncontaining 19.2 g. of dibenzo-[a,d]-cyclohepta- [1,4]-diene in 300 ml.of anhydrous tetrahydrofuran and stir the reaction mixture for 6 hoursat room temperature. Add a solution containing 12.7 g. of4-dimethylaminocyclohexanone in 50 ml. of tetrahydrofuran, warm theresulting mixture on a steam bath for three hours and allow the mixtureto stand overnight. Evaporate oil the excess tetrahydrofuran, add dilute(25%) hydrochloric acid, and separate the acid layer. To the acid layeradd sodium hydroxide to make it basic, then extract with chloroform.Evaporate off the excess solvent and distill to obtain this example.

EXAMPLE 8 5 -hydr0xy-5- (4-dimethylamin0plzenyl -dibenz0- [a,dcyclohepta-[1,41-diene A solution of g. of p-bromodimethylaniline in 400ml. of anhydrous ether is added portionwise to a suspension of 2.75 g.lithium shot in ml. of ether. The mixture is refluxed on a steam bathwith stirring for 4 hours, after which time a solution of 20.8 g. ofdibenzo-[a,d]- cyclohepta-[l,4]-diene-5-one in ml. of ether is added andthe reaction mixture is stirred and heated on the steam bath for anadditional 4 hours, and is then allowed to stand overnight. The darkpurple reaction mixture is decomposed with ice water and the organicmaterial is extracted with ether. The ether extracts are combined andextracted thoroughly with 10% aqueous hydrochloric acid and the acidextracts are combined and made basic with ammonium hydroxide solution.The precipitated product is extracted with chloroform and the chloroformis removed by concentration on the steam bath. The crude S-hydroxy 5(p-dimethylaminophenyl)-dibenzo- [a,d]-cyclohepta-[l,4]-diene residue istriturated with petroleum ether and the product is recrystallized from alarge volume of hexane after Darco clarification.

EXAMPLE 9 5 -hydr0xy-5 (4dimethylaminophenyl -dibenz0- [a,e]

cyclohepta-[1,41-triene A solution of 40 g. of p-bromodimethylaniline in400 ml. of anhydrous ether is added portionwise to a suspension of 2.75g. lithium shot in 50 ml. of ether. The mixture is refluxed on a steambath with stirring for 4 hours, after which time a solution of 20.8 g.of dibenzo-[a,e1- cyclohepta-[1,41-triene-5-one in 100 ml. of ether isadded and the reaction mixture is stirred and heated on the steam bathfor an additional 4 hours, and is then allowed to stand overnight. Thedark purple reaction mixture is decomposed with ice water and theorganic material is extracted with ether. The ether extracts arecombined and extracted thoroughly with 10% aqueous hydrochloric acid andthe acid extracts are combined and made basic with ammonium hydroxidesolution. The precipitated product is extracted with chloroform and thechloroform is removed by concentration on the steam bath. The crude5-hydroxy 5 (p-dimethylaminophenyl)-dibenzo-[a,e]-cyclohepta-[1,4]-triene residue is triturated with petroleum etherand the product is recrystallized from a large volume of hexane afterDarco clarification.

EXAMPLE 10 5 -(4 -dimelhylamin0phenyl )-dibenz0- [a,d] -cycl0hetpa-[1,4] -diene Heat a mixture containing 25 g. of 5-hydroxy-5-(4-dimethylarninophenyl)-dibenzo [a,d] cyclohepta-[1,4]- diene, 78 g. ofiodine, 39 g. of red phosphorous, 282 ml. of acetic acid and 28 ml. ofwater, at reflux temperature 1 for 3 hours with stirring. Filter theresulting hot mixture and pour the filtrate intoice water to yield ayellow precipitate. Filter and suspend in water the yellow precip'itateand make the suspension, strongly basic with sodium hydroxide. Extractthe desired product from the r 8 the group consisting -of'5-(4-dimethylaminocyclohexyl)- dibenzo-[a,d]-cyclohepta-[l,4]-dieneand, the non-toxic acid addition salts thereof.

5. The method of claim 4 wherein the daily quantity basified suspension,evaporate off the excess solvent and 5 'of active ingredient isbetweenabout- 0.1 'to '5 mg. per

recrystallize the crude product from petroleum ether to yield 5 (4'dimethylaminophenyl)-dibenzo-[ a,d] -cyc1ohepta-[1,4]-diene, M.P. 97-100C. P

I claim:

1. A composition of matter adapted when taken 10 internally to cause ananti-depressant efiect', said composition in dosage unit form comprisinga pharmaceutical carrier in admixture with between 5 an'd'lSOmg, of acompound selected from the group consistingiof-j5+(4-dmethylaminocyclohexyl) dibenzo-[a ,-d] cy'cloph [1,4]-diene and thenon-toxic acid addition '1 2. A composition of mattertadaptedwheternally to cause an anti-depressant etfectgsa' d; tion in dosage unitform comprising aflphar'm carrier in admixture with between about ifi nd5 (4 dimethylaminocyclohexyl) r-ij'dihen zo cyclohepta-[1,4]-diene. Y v1 3. 'A composition of matter-adapted whentaken-inte nally to cause ananti-depressant effect, saidf'cornpositiq in dosage unit form comprisinga pharmaceutical c rier in admixture with between about 5 and 150 ofdimethylaminocyclohexyl) dibenz o [a,d] cyclohept [1,4]-dienehydrochloride. 'i -J 4.The method of treating"psychopharmacologic'alpression which comprises administering to mammals therapeuticallyelfective does of a compound selected from kilogram of. body weight.

6.-The' method of treating psychopharmacological depression whichcomprises administering to mammals a therapeutically effective dose of5-(4-dimethylaminocyclohexyl) -diben zo- [a ,d] -cyclo hepta-[ 1,4]-diene.

7. The method of trea'ting psychopharmacological depressed mammals whichcomprises administering to mammals a therapeutically effective does of5-(4-dimethylaminocyclohexyl) dibenzo [a,d] cyclohepta [1,4]-

ene hydrochloride.

References Citedby the Examiner UNITED STATES PATENTS 11/1962 Green260570.8

2/1963 Weinstock 16765 ,1 5/1963 Pfeifier 167-65 3,098,010 7/1963Everett 1 167-65 3/1964 Bellet f260-570.8

OTHER REFERENCES Mychajlysyn: Coll. Czech. Chem. Comm, vol. 24, pp.3955-3957, 1959.

ULI N s. LEVITT, Primary Examiner.

fFR NK CACCIAPAGLIA 111., Examiner. v

4. THE METHOD OF TREATING PSHYCOPHARMACOLOGICAL DEPRESSION WHICHCOMPRISES ADMINISTERING TO MAMMALS A THERAPEUTICALLY EFFECTIVE DOES OF ACOMPOUND SELECTED FROM THE GROUP CONSISTING OF5-(4-DIMETHYLAMINOCYCLOHEXYL)DIBENZO-(A,D)-CYCLOHEPTA-(1,4)-DIENE ANDTHE NON-TOXIC ACID ADDITION SALTS THEREOF.